Ligand-accelerated catalytic asymmetric dihydroxylation using dihydroquinidine and dihydroquinidine esters as ligands

ABSTRACT

An osmium-catalyzed method of addition to an olefin. In the method of asymmetric dihydroxylation of the present invention, an olefin, a chiral ligand, an organic solvent, water, and aamine oxide and an osmium-containing compound are combined. In the method of asymmetric oxyamination of the present invention, an olefin, a chiral ligand, an organic solvent, water, an amine derivative and an osmium-containing compound are combined. In the method of asymmetric diamination of the present invention, an olefin, a chiral ligand, an organic solvent, a metallo-chloramine derivative or an amine derivative and an osmium-containing compound are combined. In one embodiment, an olefin, a chiral ligand which is a dihydroquinidine derivative or a dihydroquinine derivative, acetone, water, N-methyl morpholine N-oxide and osmium tetroxide are combined to effect asymmetric dihydroxylation of the olefin.

FUNDING

Work described herein was supported by a grant from the NationalInstitutes of Health.

RELATED APPLICATION

This is a continuation-in-part application of U.S. Ser. No. 142,692,filed Jan. 11, 1988, now abandoned.

BACKGROUND

In nature, the organic constituents of animals, microorganisms andplants are made up of chiral molecules, or molecules which exhibithandedness. Enantiomers are stereoisomers or chiral molecules whoseconfigurations (arrangements of constituent atoms) are mirror images ofeach other; absolute configurations at chiral centers are determined bya set of rules by which a priority is assigned to each substituent andare designated R and S. The physical properties of enantiomers areidentical, except for the direction in which they rotate the plane ofpolarized light: one enantiomer rotates plane-polarized light to theright and the other enantiomer rotates it to the left. However, themagnitude of the rotation caused by each is the same.

The chemical properties of enantiomers are also identical, with theexception of their interactions with optically active reagents.Optically active reagents interact with enantiomers at different rates,resulting in reaction rates which may vary greatly and, in some cases,at such different rates that reaction with one enantiomer or isomer doesnot occur. This is particularly evident in biological systems, in whichstereochemical specificity is the rule because enzymes (biologicalcatalysts) and most of the substrates on which they act are opticallyactive.

A mixture which includes equal quantities of both enantiomers is aracemate (or racemic modification). A racemate is optically inactive, asa result of the fact that the rotation of polarized light caused by amolecule of one isomer is equal to and in the opposite direction fromthe rotation caused by a molecule of its enantiomer. Racemates, notoptically active compounds, are the products of most syntheticprocedures. Because of the identity of most physical characteristics ofenantiomers, they cannot be separated by such commonly used methods asfractional distillation (because they have identical boiling points),fractional crystallization (because they are equally soluble in asolvent, unless it is optically active) and chromatography (because theyare held equally tightly on a given adsorbent, unless it is opticallyactive). As a result, resolution of a racemic mixture into enantiomersis not easily accomplished and can be costly and time consuming.

Recently, there has been growing interest in the synthesis of chiralcompounds because of the growing demand for complex organic molecules ofhigh optical purity, such as insect hormones and pheromones,prostaglandins, antitumor compounds, and other drugs. This is aparticularly critical consideration, for example, for drugs, because inliving systems, one enantiomer functions effectively and the otherenantiomer has no biological activity and/or interferes with thebiological function of the first enantiomer.

In nature, the enzyme catalyst involved in a given chemical reactionensures that the reaction proceeds asymmetrically, producing only thecorrect enantiomer (i.e., the enantiomer which is biologically orphysiologically functional). This is not the case in laboratorysynthesis, however, and, despite the interest in and energy expended indeveloping methods by which asymmetric production of a desired chiralmolecule (e.g., of a selected enantiomer) can be carried out, there hasbeen only limited success.

In addition to resolving the desired molecule from a racemate of the twoenantiomers, it is possible, for example, to produce selected asymmetricmolecules by the chiral pool or template method, in which the selectedasymmetric molecule is "built" from pre-existing, naturally-occurringasymmetric molecules. Asymmetric homogeneous hydrogenation andasymmetric epoxidation have also been used to produce chiral molecules.Asymmetric hydrogenation is seen as the first manmade reaction to mimicnaturally-occurring asymmetric reactions. Sharpless, K. B., Chemistry inBritain, January 1986, pp 38-44; Mosher, H. S. and J. D. Morrison,Science, 221:1013-1019 (1983); Maugh, T. H., Science, 221:35-354 (1983);Stinson, S., Chemistry and Engineering News, 22:24 (6/2/86).

Presently-available methods of asymmetric synthesis are limited in theirapplicability, however. Efficient catalytic asymmetric synthesisreactions are very rare; they require a directing group and thus aresubstrate limited. Because such reactions are rare and chirality can beexceptionally important in drugs, pheromones and other biologicallyfunctional compositions, a catalytic method of asymmetricdihydroxylation would be very valuable. In addition, manynaturally-occurring products are dihydroxylated or can be easily derivedfrom the corresponding derivative.

SUMMARY OF THE INVENTION

Olefins or alkenes with or without proximal heteroatom-containingfunctional groups, are asymmetrically dihydroxylated, oxyaminated ordiaminated using an osmium-catalyzed process which is the subject of thepresent invention. Chiral ligands which are novel alkaloid derivatives,particularly dihydroquinidine derivatives or dihydroquinine derivatives,useful in the method of the present invention are also the subject ofthe present invention. In the method of asymmetric modification oraddition of the present invention, an olefin, a selected chiral ligand,an organic solvent, water, an oxidant and an osmium source are combined,under conditions appropriate for reaction to occur. The method ofligand-accelerated catalysis of the present invention is useful toeffect asymmetric dihydroxylation, asymmetric oxyamination andasymmetric diamination of an olefin of interest. A particular advantageof the catalytic asymmetric method is that only small quantities ofosmium catalyst are required.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic representation of asymmetric dihydroxylation vialigand-accelerated catalysis which is carried out by the method of thepresent invention.

FIG. 2 is a schematic representation of asymmetric catalyticoxyamination of stilbene which is carried out by the method of thepresent invention.

FIG. 3 is a plot of amine concentration vs second-order-rate constant kfor the catalytic cis-dihydroxylation of styrene. At point a, no aminehas been added. Point a thus represents the rate of the catalyticprocess in the absence of added amine ligands Line b represents the rateof the catalytic process in the presence of varying amounts ofquinuclidine, a ligand which substantially retards catalysis. Line crepresents the rate of the catalytic process in the presence of thedihydroquinidine benzoate derivative 1 represented in FIG. 1. K isdefined as K_(obs) /[OsO₄ ]_(o) where rate=-[styrene]/dt=K_(obs)[styrene]. Conditions: 25 C., [OsO₄ ]_(o) =4×10⁻⁴. [NMO]_(o) =0.2M[styrene]_(o) =0.1M.

DETAILED DESCRIPTION OF THE INVENTION

Asymmetric epoxidation has been the subject of much research in the pasteight years. Earlier work demonstrated that the titanium-tartrateepoxidation catalyst is actually a complex mixture of epoxidationcatalysts in dynamic equilibrium with each other and that the mainspecies present (i.e., the 2:2 structure) is the best catalyst (i.e.,about six times more active than titanium isopropoxide bearing notartrate). This work also showed that this rate advantage is essentialto the method's success because it ensures that the catalysis ischanneled through a chiral ligand-bearing species.

The reaction of osmium tetroxide (OsO₄) with olefins is a highlyselective and reliable organic transformation. It has long been knownthat this reaction is accelerated by nucleophilic ligands. Criegee, R.et al., Annal de Chemie, 550:99 (1942); Ray, R. and D. S. Matteson,Tetrahedron Letters, 21:449-450 (1980); Herranz, E. and K. B. Sharpless,Journal of Organic Chemistry, 43:2544-2548 (1978). It has now been shownthat a highly effective osmium-catalyzed process can be used to replacepreviously known methods, such as the stoichiometric asymmetricosmylation method. Hentges, S. G. and K. B. Sharpless, Journal of theAmerican Chemical Society, 102:4263 (1980). The method of the presentinvention results in asymmetric induction and enhancement of reactionrate by binding of a selected ligand. Through the use of theligand-accelerated catalytic method of the present invention, asymmetricdihydroxylation, asymmetric diamination or asymmetric oxyamination canbe effected.

As a result of this method, two hydroxyl groups are stereospecificallyintroduced into (imbedded in) a hydrocarbon framework, resulting in cisvicinal dihydroxylation. The new catalytic method of the presentinvention achieves substantially improved rates and turnover numbers(when compared with previously-available methods), as well as usefullevels of asymmetric induction. In addition, because of the improvedreaction rates and turnover numbers, less osmium catalyst is needed inthe method of the present invention than in previously-known methods. Asa result, the expense and the possible toxicity problem associated withpreviously-known methods are reduced.

The method of the present invention is exemplified below with particularreference to its use in the asymmetric dihydroxylation of E-stilbene (C₆H₅ CH:CHC₆ H₅). The method can be generally described as presented belowand that description and subsequent exemplification not only demonstratethe dramatic and unexpected results of ligand-accelerated catalysis, butalso make evident the simplicity and effectiveness of the method.

The asymmetric dihydroxylation method of the present invention isrepresented by the scheme illustrated in FIG. 1. According to the methodof the present invention, asymmetric dihydroxylation of a selectedolefin is effected as a result of ligand-accelerated catalysis. That is,according to the method, a selected olefin is combined, underappropriate conditions, with a selected chiral ligand (which in generalwill be a chiral substituted quinuclidine), an organic solvent, water,an oxidant and osmium tetroxide. In one embodiment, a selected olefin, achiral ligand, an organic solvent, water and an oxidant are combined;after the olefin and other components are combined, OsO₄ is added. Theresulting combination is maintained under conditions (e.g., temperature,agitation, etc.) conducive for dihydroxylation of the olefin to occur.Alternatively, the olefin, organic solvent, chiral ligand, water andOsO₄ are combined and the oxidant added to the resulting combination.These additions can occur very close in time (i.e., sequentially orsimultaneously).

That is, an olefin of interest can undergo asymmetric dihydroxylationaccording to the present invention. For example, any hydrocarboncontaining at least one carbon-carbon double bond as a functional groupcan be asymmetrically dihydroxylated according to the subject method.The method is applicable to any olefin of interest and is particularlywell suited to effecting asymmetric dihydroxylation of prochiral olefins(i.e., olefins which can be converted to products exhibiting chiralityor handedness). In the case in which the method of the present inventionis used to asymmetrically dihydroxylate a chiral olefin, one enantiomerwill be more reactive than the other. As a result, it is possible toseparate or kinetically resolve the enantiomorphs. That is, through useof appropriately-selected reactants, it is possible to separate theasymmetrically dihydroxylated product from the unreacted startingmaterial and both the product and the recovered starting material willbe enantiomerically enriched. In one embodiment, an olefin of interestis combined with a chiral ligand, water, acetone and an amine oxide(which serves as the oxidant). OsO₄ is added to the combination and thedihydroxylation allowed to proceed.

The chiral ligand used in the asymmetric dihydroxylation method willgenerally be an alkaloid, or a basic nitrogenous organic compound, whichis generally heterocyclic and found widely occurring in nature. Examplesof alkaloids which can be used as the chiral ligand in the asymmetricdihydroxylation method include cinchona alkaloids, such as quinine,quinidine, cinchonine, and cinchonidine. Examples of alkaloidderivatives useful in the method of the present invention are shown inTable 1. As described in detail below, the two cinchona alkaloidsquinine and quinidine act more like enantiomers than likediastereometers in the scheme represented in Figure 1.

As represented in FIG. 1, and as shown by the results in Table 2,dihydroquinidine derivatives (represented as DHQD) and dihydroquininederivatives (represented as DHQ) have a pseudo-enantiomeric relationshipin the present method (DHQD and DHQ are actually diastereometers). Thatis, they exhibit opposite enantiofacial selection. Such derivatives willgenerally be esters, although other forms can be used. Whendihydroquinidine is used as the ligand, delivery of the two hydroxylgroups takes place from the top or upper face (as represented in FIG. 1)of the olefin which is being dihydroxylated. That is, in this casedirect attack of the re- or re,re- face occurs. In contrast, when thedihydroquinine derivative is the ligand used, the two hydroxyl groupsare delivered from the bottom or lower (si- or si,si-face) face of theolefin, again as represented in FIG. 1. This is best illustrated byreference to entries 1, 2 and 5 of Table 2. As shown, when DHQD(dihydroquinidine esters) is used, the resulting diol has an R or R,Rconfiguration and when ligand 2 (dihydroquinine esters) is used, theresulting diol has an S or S,S configuration.

                  TABLE 1                                                         ______________________________________                                        Alkaloid Derivatives                                                          R              Derivative    Yield %  % ee                                    ______________________________________                                        3-ClPH         3-chlorobenzoyl                                                                             89       96.5                                                   dihydroquinidine                                               2-MeOPh        2-methoxybenzoyl                                                                            89       96                                                     dihydroquinidine                                               3-MeOPh        3-methoxybenzoyl                                                                            87       96.7                                                   dihydroquinidine                                               2-NPht         2-naphtoyl    95.4     98.6                                                   dihydroquinidine                                                ##STR1##      cyclohexanoyl dihydroquinidine                                  ##STR2##      p-phenylbenzoyl dihydroquinidine                               Me             Acetyl        72       94                                                     dihydroquinidine                                               Me.sub.2 N     dimethylcarbamoyl                                                                           96       95                                                     dihydroquinidine                                               Ph             benzoyl       92       98                                                     dihydroquinidine                                               4-MeOPh        4-methoxybenzoyl                                                                            91       97.6                                                   dihydroquinidine                                               4-ClPh         4-chlorobenzoyl                                                                             93       99                                                     dihydroquinidine                                               2-ClPh         2-chlorobenzoyl                                                                             87       94.4                                                   dihydroquinidine                                               4-NO.sub.2 Ph  4-nitro benzoyl                                                                             71       93                                                     dihydroquinidine                                               ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                                             ligand; ee;                                              olefin               conign. of diol                                                                            time                                        ______________________________________                                         ##STR3##            DHQD; 52%; R DHQ; 53.6%; S                                                                 3 h                                          ##STR4##            DHQD; 65%; RR DHQ; 55.4%; SS                                                               5 h                                          ##STR5##            DHQD; 33%; R 1.5 h                                        ##STR6##            DHQD; 76%; RR                                                                              7 h                                          ##STR7##            DHQD; 88%; RR DHQ; 78.5%; SS                                                               7 h                                          ##STR8##            DHQD; 65%;   3 h                                          ##STR9##            DHQD; 51%    5 h                                          ##STR10##           DHQD; 67%    1 h                                          ##STR11##           DHQD; 20%    1.5 h                                        ##STR12##           DHQD; 20%; RR                                                                              17 h                                         ##STR13##           DHQD; 46%; R 1 h                                          ##STR14##           DHQD; 68%                                                 ##STR15##           DHQD; 80%                                                 ##STR16##           DHQD; 34%                                                 ##STR17##           DHQD; 74.3%                                               ##STR18##           DHQD; 34%                                                 ##STR19##           DHQD; 50%                                                 ##STR20##           DHQD; 38%                                                 ##STR21##           DHQD; 0-10%                                               ##STR22##           DHQD; 4.4%                                               ______________________________________                                        olefin               ligand; ee                                               ______________________________________                                         ##STR23##           DHQD; (ca. 10%)                                           ##STR24##           DHQD; (53%)                                               ##STR25##           DHQD; (63%)                                               ##STR26##           DHQD; (ca 5%)                                             ##STR27##           DHQD; (45%)                                               ##STR28##           DHQD; (53%)                                               ##STR29##           DHQD; (ca. 12%)                                           ##STR30##           DHQD; (27%)                                              ______________________________________                                                             ligand; ee;                                              olefin               conign. of diol                                                                            time                                        ______________________________________                                         ##STR31##           DHQD                                                      ##STR32##           DHQD                                                      ##STR33##           DHQD                                                      ##STR34##           DHQD; 37.5%                                               ##STR35##           DHQD; 45%                                                 ##STR36##           DHQD                                                     ______________________________________                                    

Because of this face selection rule or phenomenon, it is possible,through use of the present method and the appropriate chiral ligand, topre-determine the absolute configuration of the dihydroxylation product.

As is also evident in Table 2, asymmetric dihydroxylation of a widevariety of olefins has been successfully carried out by means of thepresent invention. In each of the cases represented in the Table, theface selection "rule" (as interpreted with reference to the orientationrepresented in FIG. 1) applied: use of DHQD resulted in attack ordihydroxylation occurring from the top or upper face and use of DHQresulted in attack or dihydroxylation occurring from the bottom or lowerface of the olefin. This resulted, respectively, in formation ofproducts having an R or R,R configuration and products having an S orS,S configuration.

In general, the concentration of the chiral ligand used will range from0.01 M to 2.0 M. In one embodiment, exemplified below, the solution is0.261 M in alkaloid 1 (the dihydroquinidine derivative). In oneembodiment of the method, carried out at room temperature, theconcentrations of both alkaloids represented in FIG. 1 are at 0.25 M. Inthis way, the enantiomeric excess resulting under the conditions used ismaximized. The amount of chiral ligand necessary for the method of thepresent invention can be varied as the temperature at which the reactionoccurs varies. For example, it is possible to reduce the amount ofalkaloid (or other chiral ligand) used as the temperature at which thereaction is carried out is changed. For example, if it is carried out,using the dihydroquinidine derivative, at 0° C., the alkaloidconcentration can be 0.15 M. In another embodiment, carried out at 0°C., the alkaloid concentration was 0.0625 M.

Many oxidants (i.e., essentially any source of oxygen) can be used inthe present method. For example, amine oxides (e.g., trimethyl amineoxides), tert-butyl hydroperoxide, hydrogen peroxide, and oxygen plusmetal catalysts (e.g., copper (Cu+-Cu++/O₂), platinum (Pt/O₂), palladium(Pd/O₂) can be used. In one embodiment of the invention,N-methylmorpholine N-oxide (NMO) is used as the oxidant. NMO isavailable commercially (e.g., Aldrich Chemicals, 97% NMO anhydrous).

Osmium will generally be provided in the method of the present inventionin the form of osmium tetroxide (OsO₄), although other sources (e.g.,osmium trichloride anhydrous, osmium trichloride hydrate) can be used.OsO₄ can be added as a solid or in solution.

The osmium catalyst used in the method of the present invention can berecycled, for re-use in subsequent reactions. This makes it possible notonly to reduce the expense of the procedure, but also to recover thetoxic osmium catalyst. For example, the osmium catalyst can be recycledas follows: Using reduction catalysts (e.g., Pd-C), the osmium VIIIspecies is reduced and adsorbed onto the reduction catalyst. Theresulting solid is filtered and resuspended. NMO (or an oxidant), thealkaloid and the substrate (olefin) are added, with the result that theosmium which is bound to the Pd/C solid is reoxidized to OsO₄ andre-enters solution and plays its usual catalytic role in formation ofthe desired diol. This procedure (represented below) can be carried outthrough numerous cycles, thus re-using the osmium species. The palladiumor carbon can be immobilized, for example, in a fixed bed or in acartridge. ##STR37##

In one embodiment an olefin, such as recrystallised trans-stilbene (C₆H₅ CH:CHC₆ H₅), is combined with a chiral ligand (e.g., p-chlorobenzoylhydroquinidine), acetone, water and NMO. The components can be addedsequentially or simultaneously and the order in which they are combinedcan vary. In this embodiment, after the components are combined, theresulting combination is cooled (e.g., to approximately 0° C. in thecase of trans-stilbene); cooling can be carried out using an ice-waterbath. OsO₄ is then added (e.g., by injection), in the form of a solutionof OsO₄ in an organic solvent (e.g., in toluene). After addition ofOsO₄, the resulting combination is maintained under conditionsappropriate for the dihydroxylation reaction to proceed.

The method of the present invention can be carried out over a widetemperature range and the limits of that range will be determined, forexample, by the limit of the organic solvent used. The method can becarried out, for example, in a temperature range from room temperatureto -10 C. Concentrations of individual reactants (e.g., chiral ligand,oxidant, etc.) can be varied as the temperature at which the method ofthe present invention is carried out. The saturation point (e.g., theconcentration of chiral ligand at which results are maximized) istemperature-related. As explained previously, for example, it ispossible to reduce the amount of alkaloid used when the method iscarried out at lower temperatures.

The organic solvent used in the present method can be, for example,acetone, acetonitrile, THF, DME, ethanol, methanol, pinacolone, tertbutanol or a mixture of two or more organic solvents.

Using the methods described in the Exemplification, HPLC analysisdemonstrated that the enantiomeric excess of the resulting diol was 78%.

In another embodiment of the present invention, styrene was combinedwith a chiral ligand (DHQD), acetone, water and NMO and OsO₄. The plotof amine concentration vs second-order-rate-constant K for the catalyticcis-dihydroxylation of styrene is represented in FIG. 2. The kineticdata of FIG. 2 clearly shows the dramatic effect of ligand-acceleratedcatalysis achieved by use of the method of the present invention. Pointa in FIG. 2 represents the rate of the catalytic process in the absenceof amine ligands (t1/2=108 minutes). Line b shows the rates of theprocess in the presence of varying amounts of quinuclidine, a ligandwhich substantially retards catalysis (at greater than 0.1Mquinuclidine, t1/2 is greater than 30 hours). Because of the observedretarding effect of quinuclidine (ligand-decelerated catalysis) theresult represented by line C was unexpected. That is, when the processoccurs in the presence of dihydroquinidine benzoate derivative 1 (seeFIG. 1), the alkaloid moiety strongly accelerates the catalytic processat all concentrations (with ligand 1=0.4 M, t1/2=4.5 minutes), despitethe presence of the quinuclidine moiety.

The rate of the stoichiometric reaction of styrene with osmium tetroxideand that of the corresponding catalytic process were compared. Thecomparison indicates that both have identical rate constants [K_(stoic)(5.1±0.1)×10² M⁻¹ min⁻¹ and K_(cat) =(4.9±0.4)×10² M⁻¹ min⁻¹ ], and thatthey undergo the same rate acceleration upon addition of ligand 1.Hydrolysis and reoxidation of the reduced osmium species, steps whichaccomplish catalyst turnover, are not kinetically significant in thecatalytic process with styrene. It may be concluded that the limitingstep is the same in both processes and consists of the initial additionreaction forming the osmate ester. A detailed mechanistic study revealsthat the observed rate acceleration by added ligand 1 is due toformation of an osmium tetroxidealkaloid complex which, in the case ofstyrene, is 23 times more reactive than free osmium tetroxide. The ratereaches a maximal and constant value beyond an (approximate) 0.25 Mconcentration of ligand 1. The onset of this rate saturation correspondsto a pre-equilibrium between DHQD and osmium tetroxide with a ratherweak binding constant (K_(eq) =18 ±2M⁻¹). Increasing the concentrationof above 0.25 M does not result in corresponding increases in theenantiomeric excess of the product diol. At this concentration ofalkaloid, virtually all of the osmium tetroxide already exists asalkaloid complex and raising the concentration further has littleeffect.

At least in the case of styrene, the rate acceleration in the presenceof the alkaloid is accounted for by facilitation of the initialosmylation step. The strikingly opposite effects of quinuclidine andDHQD on the catalysis can be related to the fact that althoughquinuclidine also accelerates the addition of osmium tetroxide toolefins, it binds too strongly to the resulting osmium(VI) esterintermediate and inhibits catalyst turnover by retarding thehydrolysis/reoxidation steps of the cycle. In contrast the alkaloidappears to achieve a balancing act which renders it near perfect for itsrole as an accelerator of the dihydroxylation catalysis. It bindsstrongly enough to accelerate addition to olefins, but not so tightlythat it interferes (as does quinuclidine) with subsequent stages of thecatalytic cycle. Chelating tertiary amines [e.g., 2,2'-bipyridine and(-)-(R,R)-N,N,N',N'-tetramethyl-1,2-cyclohexanediamine) at 0.2 Mcompletely inhibit the catalysis. Pyridine at 0.2 M has the same effect.

As represented in Table 2, the method of the present invention has beenapplied to a variety of olefins. In each case, the face selection ruledescribed above has been shown to apply (with reference to theorientation of the olefin as represented in FIG. 1). That is, in thecase of the asymmetric dihydroxylation reaction in which thedihydroquinidine derivative is the chiral ligand, attack occurs on there- or re,re- face) and in the case in which the dihydroquininederivative is the chiral ligand, attack occurs on the si- or si,si-face. Thus, as demonstrated by the data presented in the Table 2, themethod of the present invention is effective in bringing about catalyticasymmetric dihydroxylation; in all cases, the yield of the diol was80-95%.

The method of the present invention is also useful to effect asymmetricvicinal diamination and asymmetric vicinal oxyamination of an olefin. Inthe case of substitution of two nitrogen or of a nitrogen and oxygen, anamino derivative is used as an amino transfer agent and as an oxidant.For example, the olefin to be modified, an organic solvent, water, achiral ligand, an amino derivative and an osmium-containing compound arecombined and the combination maintained under conditions appropriate forthe reaction to occur. The amino derivative can be, for example, anN-chlorocarbamate or chloroamine T. Asymmetric catalytic oxyamination ofrecrystallized trans stilbene, according to the method of the presentinvention, is represented in FIG. 2.

EXAMPLE I Asymmetric Dihydroxylation of Stilbene

The following were placed sequentially in a 2 L bottle (or flask): 180.2g (1.0 M) of recrystallised trans stilbene (Aldrich 96%), 62.4 g (0.134moles; 0.134 eq) of the p-chlorobenzoate of hydroquinidine (1), 450 mLof acetone, 86 mL of water (the solution is 0.261 M in alkaloid 1) and187.2 g (1.6 mol, 1.6 eq.) of solid N-Methylmorpholine N-Oxide (NMO,Aldrich 97%). The bottle was capped, shaken for 30 seconds, cooled to0°-4° C. using an ice-water bath. OsO₄ (4.25 mL of a solution preparedusing 0.120 g OsO₄ /mL toluene; 0.002 Mol %; 0.002 eq.) was injected.The bottle was shaken and placed in a refrigerator at ca. 4° C. withoccasional shaking. A dark purple color developed and was slowlyreplaced by a deep orange one; the heterogeneous reaction mixturegradually became homogeneous and at the end of the reaction, a clearorange solution was obtained. The reaction can be conveniently monitoredby TLC (silicagel; CH₂ Cl₂ ; disappearance of the starting material at adefined Rf). After 17 hours, 100g of solid sodium metabisulfite (Na₂ S₂O₅) were added, the reaction mixture was shaken (1 minute) and left at20° C. during 15 minutes. The reaction mixture was then diluted by anequal volume of CH₂ Cl₂ and anhydrous Na₂ SO₄ added (100 g). Afteranother 15 minutes, the solids were removed by filtration through a padof celite, washed three times with 250 mL portions of CH₂ Cl₂ and thesolvent was evaporated under vacuum (rotatory-evaporator, bathtemperature=30°-35° C.)

The crude oil was dissolved in ethyl acetate (750 mL), extracted threetimes with 500 ml. portions of 2.0 M HCl, once with 2.0 M NaOH, driedover Na₂ SO₄ and concentrated in vacuo to leave 190 g (89%) of crudediol 2 as a pale yellow solid. The enantiomeric excess of the crude diol2 was determined by HPLC analysis of the derived bis-acetate (Pirkle 1Acolumn using 5% isopropanol/hexane mixture as eluant. Retention timesare: t1=18.9 minutes; t2=19.7 minutes. Recrystallisation from about 1000ml. CH₂ Cl₂ gave 150 g (70%) of pure diol 2 (ee=90%). ee (enantiomericexcess) is calculated from the relationship (for the R enantiomer, forexample): percent e.e.=[(R)-(S)/[(R)+(S)]×100.

The aqueous layer was cooled to 0° C. and treated with 2.0 M NaOH (about500 mL) until pH=7. Methylene chloride was added (500 mL) and the pHadjusted to 10-11 using more 2.0 M NaOH (about 500 mL). The aqueouslayer was separated, extracted twice with methylene chloride (2×300 mL)and the combined organic layers were dried over Na₂ SO₄. The solvent wasremoved in vacuo to provide the alkaloid 1 as a yellow foam. The crudealkaloid was dissolved in ether (1000 mL), cooled to 0° C. (ice-bath)and treated with dry HCl until acidic pH (about 1-2). The faint yellowprecipitate of p-chlorobenzoylhydroquinidine hydrochloride was collectedby filtration and dried under high vacuum (0.01 mm Hg).

The free base was liberated by suspending the salt in ethyl acetate (500mL), cooling to 0° C. and adding 28% NH₄ OH until pH=11 was reached.After separation, the aqueous layer was extracted twice with ethylacetate, the combined organic layers were dried over Na₂ SO₄ and thesolvent removed in vacuo to give the free base as a white foam.

EXAMPLE 2 Asymmetric Dihydroxylation of Stilbene

Asymmetric dihydroxylation of stilbene was carried out as described inExample 1, except that 1.2 equivalents of NMO were used.

EXAMPLE 3 Asymmetric Dihydroxylation of Stilbene

Asymmetric dihydroxylation of stilbene was carried out as described inExample 1, except that 1.2 equivalents of NMO, as a 62% wt. solution,were used.

EXAMPLE 4 Preparation of dihydroquinidine derivative Preparation ofdihydroquinidine by catalytic reduction of quinidine

To a solution of 16.2 g of quinidine (0.05 mol) in 150 mL of 10% H₂ SO₄(15 g conc H₂ SO₄ in 150mL H₂ O) was added 0.2 g of PdCl₂ (0.022eq;0.0011 mol). The reaction mixture was hydrogenated in a Parr shaker at50 psi pressure. After 2 h, the catalyst was removed by filtrationthrough a pad of celite and washed with 150 mL of water. The faintyellow solution so obtained was slowly added to a stirred aqueous NaOHsolution (15 g of NaOH in 150 mL H₂ O. A white precipitate immediatelyformed and the pH of the solution was brought to 10-11 by addition ofexcess aqueous 15% NaOH. The precipitate was collected by filtration,pressed dry and suspended in ethanol (175 mL). The boiling solution wasquickly filtered and upon cooling to room temperature, white needlescrystallized out. The crystals were collected and dried under vacuum(90° C.; 0.05 mm Hg) overnight. This gave 8.6 g (52.7%) of puredihydroquinidine mp=169.5°-170° C. The mother liquor was placed in afreezer at 15° C. overnight. After filtration and drying of thecrystals, another 4.2 g (21.4%) of pure material was obtained, raisingthe total amount of dihydroquinidine to 12.8 g (74.1%).

Preparation of dihydroquinidine p-chlorobenzoate (ligand 1) Fromdihydroquinidine hydrochloride (Aldrich)

To a cooled (0° C.) suspension of 100 g dihydroquinidine hydrochloride(0.275 mol) in 300 mL of dry CH₂ Cl₂ was added, over 30 minutes withefficient stirring, 115 mL of Et₃ N (0.826 eq; 3 eqs) dissolved in 50 mLof CH₂ Cl₂. The dropping funnel was rinsed with an additional 20 mL ofCH₂ Cl₂. After stirring 30 minutes at 0° C., 42 mL of p-chlorobenzoylchloride (0.33 mol;57.8 g; 1.2 eq) dissolved in 120 mL of CH₂ Cl₂ wasadded dropwise over a period of 2 h. The heterogeneous reaction mixturewas then stirred 30 minutes at 0° C. and 1 hour at room temperature; 700mL of a 3.0M NaOH solution was then slowly added until pH=10-11 wasobtained. After partitioning, the aqueous layer was extracted with three100 mL portions of CH₂ Cl₂. The combined organic layers were dried overNa₂ SO₄ and the solvent removed in vacuo (rotatory evaporator). Thecrude oil was dissolved in 1 L of ether, cooled to 0° C. and treatedwith HCl gas until the ether solution gives a pH of about 2 using wet pHpaper. The slightly yellow precipitate was collected and dried undervacuum to give 126 g (91.5%) of dihydroquinidine p-chlorobenzoatehydrochloride.

The salt was suspended in 500 mL of ethyl acetate, cooled to 0° C. andtreated with 28% NH₄ OH until pH=11 was reached. After separation, theaqueous layer was extracted with two 200 mL portions of ethyl acetate.The combined organic layers were dried over Na₂ SO₄ and the solventremoved under vacuum, leaving the free base 1 as a white foam (112 g;88% overall). [a]²⁵ D-59.1° (c 1.0, EtOH); IR (CH₂ Cl₂) 2940, 2860,1720, 1620, 1595, 1520, 1115, 1105, 1095, 1020 cm⁻¹ ; ¹ H NMR (CDCl₃)8.72 (d, 1H, J=5Hz), 8.05 (br d, 3H, J=9.7Hz), 7.4 (m, 5H), 6.72 (d, 1H,J=7.2Hz), 3.97 (s, 3H), 3.42 (dd, 1H, J=9, 19.5 Hz), 2.9-2.7 (m, 4H),1.87 (m, 1H), 1.75 (br s, 1H), 1.6-1.45 (m, 6H), 0.92 (t, 3H, J=7Hz).Anal. Calcd for C₂₇ H₂₉ ClN₂ O₃ : C, 69.74; H, 6.28; Cl, 7.62; N, 6.02.Found: C, 69.95;H, 6.23; Cl, 7.81; N, 5.95.

From dihydroquinidine

To a 0° C. solution of 1.22 g dihydroquinidine (0.0037 mol) in 30 mL ofCH₂ Cl₂ was added 0.78 mL of Et₃ N (0.0056 mol; 1.5 eq), followed by0.71 mL of p-chlorobenzoyl chloride (0.005 mol; 1.2 eq) in 1 mL CH₂ Cl₂.After stirring 30 minutes at 0° C. and 1 hour at room temperature, thereaction was quenched by the addition of 10% Na₂ CO₃ (20 mL). Afterseparation, the aqueous layer was extracted with three 10 mL portions ofCH₂ Cl₂. The combined organic layers were dried over Na₂ SO₄ and thesolvent removed under vacuum. The crude product was purified asdescribed above. Dihydroquinidine p-chlorobenzoate (1) was obtained in91% yield (1.5g) as a white foam.

Recovery of dihydroquinidine p-chlorobenzoate

The aqueous acidic extracts (see EXAMPLE 1) were combined, cooled to 0°C. and treated with 2.0M NaOH solution (500 mL) until pH=7 was obtained.Methylene chloride was added (500 mL) and the pH was adjusted to 10-11using more 2.0M NaOH. The aqueous layer was separated and extracted withtwo 300 mL portions of CH₂ Cl₂. The combined organic layers were driedover Na₂ SO₄ and concentrated to leave the crude alkaloid as a yellowfoam. The crude dihydroquinidine p-chlorobenzoate (1) was dissolved in 1L of ether, cooled to 0° C. and HCl gas was bubbled into the solutionuntil a pH of 1-2 was obtained using wet pH paper. The pale yellowprecipitate of 1 as the hydrochloride salt was collected by filtrationand dried under high vacuum (0.01 mm Hg). The free base was liberated bysuspending the salt in 500 mL of ethyl acetate, cooling theheterogeneous mixture to 0 ° C. and adding 28% NH ₄ OH (or 15% NaOH)until pH=11 was obtained. After separation, the aqueous layer wasextracted with two 100 mL portions of ethyl acetate, the combinedorganic layers were dried over Na₂ SO₄ and the solvent removed in vacuoto give 56 g (91% recovery) of pure dihydroquinidine p-chlorobenzoate(1) as a white foam.

EXAMPLE 5 Preparation of dihydroquinine derivative Preparation ofdihydroquinine p-chlorobenzoate

The catalytic hydrogenation and p-chlorobenzoylation were conducted asdescribed for the dihydroquinidine p-chlorobenzoate. The physicalproperties of dihydroquinine p-chlorobenzoate 2 are as follows: [a]²⁵D+142.1 (c 1.0, EtOH); IR (CH₂ Cl₂) 2940, 2860, 1720, 1620, 1595, 1508,1115, 1105, 1095, 1020 cm⁻¹, ¹ H NMR (CDCl₃) d 8.72 (d, 1H, J=5 Hz),8.05 (br d, 3H, J=8 Hz), 7.4 (m, 5H), 6.7 (d, 1H, J=8 Hz), 4.0 (s, 3H),3.48 (dd, 1H, J=8.5, 15.8 Hz), 3.19 (m, 1H), 3.08 (dd, 1H, J=11, 15 Hz),2.69 (ddd, 1H, J=5, 12, 15.8 Hz), 2.4 (dt, 1H, J=2.4, 15.8Hz), 1.85-1.3(m, 8H), 0.87 (t, 3H, J=Hz). Anal. Calcd for C.sub. 27 H₂₉ ClN₂ O₃ : C,69.74; H, 6.28; Cl, 7.62; N, 6.02. Found: C, 69.85; H, 6.42; Cl, 7.82;N, 5.98.

Recovery of dihydroquinine p-chlorobenzoate (2)

The procedure is identical to that described above for recovery of 1.

Equivalents

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific substances and procedures described herein. Such equivalentsare considered to be within the scope of this invention, and are coveredby the following claims.

We claim:
 1. An alkaloid derivative selected from the group consistingof:a. dimethylcarbamoyl dihydroquinidine b. benzoyl dihydroquinidine; c.4-methoxybenzoyl dihydroquinidine; d. 4-chlorobenzoyl dihydroquinidine;e. 2-chlorobenzoyl dihydroquinidine; f. 4-nitrobenzoyl dihydroquinidine;g. 3-chlorobenzoyl dihydroquinidine; h. 2-methoxybenzoyldihydroquinidine; i. 3-methoxybenzoyl dihydroquinidine; j. 2-naphtoyldihydroquinidine; k. cyclohexanoyl dihydroquinidine; l. p-phenylbenzoyldihydroquinidine; m. dimethylcarbamoyl dihydroquinine; n. benzoyldihydroquinine; o. 4-methoxybenzoyl dihydroquinine; p. 4-chlorobenzoyldihydroquinine; q. 2-chlorobenzoyl dihydroquinine; r. 4-nitrobenzoyldihydroquinine; s. 3-chlorobenzoyl dihydroquinine; t. 2-methoxybenzoyldihydroquinine; u. 3-methoxybenzoyl dihydroquinine; v. 2-naphtoyldihydroquinine; w. cyclohexanoyl dihydroquinine; and x. p-phenylbenzoyldihydroiquinone.
 2. A dihydroquinidine ester of the formula ##STR38##wherein R' is p-chlorobenzoyl and Ar is ##STR39##
 3. A dihydroquinoneester of the formula ##STR40## wherein R' is p-chlorobenzoyl and Ar is##STR41##